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Phenytoin and Rifampin Do Not Decrease Levels in Acute Tacrolimus Toxicity
Benjamin O Lawson1, Heemesh Seth1, Dan Quan2,3
1Honor Health, Internal Medicine Residency, Scottsdale, AZ, USA.
Abstract:
Tacrolimus is used in bone marrow transplant patients to prevent graft-versus-host disease. There have been few case reports of tacrolimus toxicity (>30 ng/mL) in solid organ recipients as well as in nontransplant patients. Several case reports suggest phenytoin and rifampin decrease tacrolimus levels in toxicity, but does it actually make a difference? A 60-year-old man with acute myeloblastic leukemia after allogenic stem cell transplant with fever, diarrhea, and abdominal pain was transferred to the intensive care unit for persistent hypotension and acute hypoxic respiratory failure requiring intubation. The following day his tacrolimus level was 8.6 ng/mL and creatinine was 2.2 (baseline = 1.8). The patient inadvertently received 15 mg intravenous tacrolimus instead of his scheduled 0.5 mg intravenous. Four hours later, a random tacrolimus level was 36.4 ng/mL. Tacrolimus was discontinued; phenytoin 200 mg BID was started for 4 doses and rifampin was started for 2 doses at 600 mg. Sixteen hours postinjection, tacrolimus level decreased to 26.4 ng/mL and to 9 ng/mL after 64 hours. Creatinine improved to 1.1 after 30 hours. He was extubated 5 days later without any new neurological findings and his creatinine returned to baseline. Our patient received 30 times his daily dose resulting high tacrolimus levels. Assuming there was sufficient time for distribution, our patient's half-life increased to 34.5 hours compared with the reported half-life of 12 hours. The possibilities for this increase include ineffective or harmful effects of the phenytoin/rifampin combination, change in metabolism kinetics at high levels, or other unidentified patient-specific factors. Further studies should be done to ensure that phenytoin and rifampin are safe to give in tacrolimus toxicity.
Insights
High tacrolimus levels from an accidental overdose in a stem cell transplant patient showed a prolonged half-life. The combination of phenytoin and rifampin
Area of Science:
- Pharmacology
- Transplantation Medicine
- Toxicology
Background:
- Tacrolimus is a crucial immunosuppressant for preventing graft-versus-host disease in bone marrow transplant recipients.
- Tacrolimus toxicity, defined as levels >30 ng/mL, is rare but reported in solid organ transplant and non-transplant patients.
- Phenytoin and rifampin are suggested to reduce tacrolimus levels during toxicity, but their efficacy requires further investigation.
Purpose of the Study:
- To report a case of severe tacrolimus toxicity due to inadvertent overdose in an allogeneic stem cell transplant patient.
- To evaluate the impact of phenytoin and rifampin administration on tacrolimus levels and patient outcomes.
- To investigate potential factors contributing to an altered tacrolimus half-life during toxicity.
Main Methods:
- A 60-year-old acute myeloblastic leukemia patient post-allogeneic stem cell transplant received an accidental 30-fold overdose of intravenous tacrolimus.
- Tacrolimus levels, creatinine, and clinical status were monitored post-overdose.
- Phenytoin and rifampin were administered to manage the high tacrolimus levels.
Main Results:
- The patient's tacrolimus level peaked at 36.4 ng/mL four hours after the overdose.
- Following administration of phenytoin and rifampin, tacrolimus levels decreased to 26.4 ng/mL after 16 hours and 9 ng/mL after 64 hours.
- The patient's estimated tacrolimus half-life increased to 34.5 hours, compared to the typical 12 hours, with subsequent improvement in creatinine and clinical status.
Conclusions:
- This case highlights a significant increase in tacrolimus half-life following a massive overdose.
- The effectiveness and safety of the phenytoin and rifampin combination in managing tacrolimus toxicity remain uncertain.
- Further research is warranted to elucidate the factors influencing tacrolimus metabolism and half-life during toxicity and to confirm the safety of co-administered drugs.
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